Abstract
ABSTRACTRomosozumab is a newly available treatment for osteoporosis acting by sclerostin inhibition. Its cardiovascular safety has been questioned after finding excess cardiovascular disease (CVD)‐related events in a pivotal phase 3 trial. Previous studies of relationships between circulating sclerostin levels and CVD and associated risk factors have yielded conflicting findings, likely reflecting small numbers and selected patient groups. We aimed to characterize relationships between sclerostin and CVD and related risk factors in more detail by examining these in two large cohorts, Ludwigshafen Risk and Cardiovascular Health study (LURIC; 34% female, mean age 63.0 years) and Avon Longitudinal Study of Parents and Children study (ALSPAC) mothers (mean age 48.1 years). Together these provided 5069 participants with complete data. Relationships between sclerostin and CVD risk factors were meta‐analyzed, adjusted for age, sex (LURIC), body mass index, smoking, social deprivation, and ethnicity (ALSPAC). Higher sclerostin levels were associated with higher risk of diabetes mellitus (DM) (odds ratio [OR] = 1.25; 95% confidence interval [CI] 1.12, 1.37), risk of elevated fasting glucose (OR 1.15; CI 1.04, 1.26), and triglyceride levels (β 0.03; CI 0.00, 0.06). Conversely, higher sclerostin was associated with lower estimated glomerular filtration rate (eGFR) (β −0.20; CI −0.38, −0.02), HDL cholesterol (β −0.05; CI −0.10, −0.01), and apolipoprotein A‐I (β −0.05; CI −0.08, −0.02) (difference in mean SD per SD increase in sclerostin, with 95% CI). In LURIC, higher sclerostin was associated with an increased risk of death from cardiac disease during follow‐up (hazard ratio [HR] = 1.13; 1.03, 1.23) and with severity of coronary artery disease on angiogram as reflected by Friesinger score (0.05; 0.01, 0.09). Associations with cardiac mortality and coronary artery severity were partially attenuated after adjustment for risk factors potentially related to sclerostin, namely LDL and HDL cholesterol, log triglycerides, DM, hypertension, eGFR, and apolipoprotein A‐I. Contrary to trial evidence suggesting sclerostin inhibition leads to an increased risk of CVD, sclerostin levels appear to be positively associated with coronary artery disease severity and mortality, partly explained by a relationship between higher sclerostin levels and major CVD risk factors. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Highlights
Sclerostin is a WNT inhibitor secreted by osteocytes, which acts to inhibit osteoblast activity as part of bone’s adaptive response to mechanical loading.[1]
Higher sclerostin levels were found to be associated with higher risk of cardiovascular mortality in 98 chronic kidney disease (CKD) patients on peritoneal dialysis,(9) 173 non-dialysed CKD patients,(10) and 130 participants with type 2 diabetes mellitus (T2DM)/prevalent CVD.[11]. On the other hand, higher sclerostin levels were found to be associated with reduced cardiovascular mortality in 673 renal dialysis patients.[12]. These findings are in line with previous studies indicating relationships between bone and cardiovascular disease.[13]. In terms of how sclerostin might influence CVD risk, sclerostin levels are related to a number of CVD risk factors
Results were available from 2054 participants (34% female) from Ludwigshafen Risk and Cardiovascular Health (LURIC) and 3015 from ALSPAC mothers (Supplemental Fig. S1; Tables 1 and 2). {TBL 1}{TBL 2} LURIC participants had a mean age of 63.0 years, of whom 76% had a clinical diagnosis of coronary artery disease (CAD), and 16% subsequently died as a result of cardiac disease over a mean follow-up of 9.9 years
Summary
Sclerostin is a WNT inhibitor secreted by osteocytes, which acts to inhibit osteoblast activity as part of bone’s adaptive response to mechanical loading.[1]. Whereas excess cardiovascular events were found in the romosozumab treatment arm compared with those treated with alendronic acid in the ARCH study[5] and in men treated with romosozumab versus placebo,(6) no excess was observed in the FRAME study, where the comparator group consisted of placebo.[4] These divergent findings may reflect a protective influence of bisphosphonates on CVD risk, as opposed to an adverse effect of romosozumab Another bisphosphonate, zoledronate, has been found to decrease all-cause mortality, to which reduced cardiovascular mortality may contribute.[7] a beneficial effect on mortality was not born out in a meta-analysis of drug trials of zoledronate and other bisphosphonates.[8]. Sclerostin levels were reported to be higher in 40 T2DM patients compared with age-matched controls,(14) consistent with the recognized relationship between T2DM and fracture risk .15-17 Sclerostin levels have been found to be increased in CKD patients, reflecting an inverse relationship between glomerular filtration rate (GFR) and sclerostin levels, which is not explained by reduced renal elimination.[18]
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